title: MYC cooperates with AKT in prostate tumorigenesis and alters sensitivity to mTOR inhibitors.
abstract: MYC and phosphoinositide 3-kinase (PI3K)-pathway deregulation are common in human prostate cancer. Through examination of 194 human prostate tumors, we observed statistically significant co-occurrence of MYC amplification and PI3K-pathway alteration, raising the possibility that these two lesions cooperate in prostate cancer progression. To investigate this, we generated bigenic mice in which both activated human AKT1 and human MYC are expressed in the prostate (MPAKT/Hi-MYC model). In contrast to mice expressing AKT1 alone (MPAKT model) or MYC alone (Hi-MYC model), the bigenic phenotype demonstrates accelerated progression of mouse prostate intraepithelial neoplasia (mPIN) to microinvasive disease with disruption of basement membrane, significant stromal remodeling and infiltration of macrophages, B- and T-lymphocytes, similar to inflammation observed in human prostate tumors. In contrast to the reversibility of mPIN lesions in young MPAKT mice after treatment with mTOR inhibitors, Hi-MYC and bigenic MPAKT/Hi-MYC mice were resistant. Additionally, older MPAKT mice showed reduced sensitivity to mTOR inhibition, suggesting that additional genetic events may dampen mTOR dependence. Since increased MYC expression is an early feature of many human prostate cancers, these data have implications for treatment of human prostate cancers with PI3K-pathway alterations using mTOR inhibitors.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Clegg
authors.forename: Suzana S
authors.initials: SS
authors.lastname: Couto
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.forename: Haley
authors.initials: H
authors.lastname: Hieronymus
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Katharine
authors.initials: K
authors.lastname: Ellwood-Yen
authors.forename: William L
authors.initials: WL
authors.lastname: Gerald
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology; D011467:Prostate / Q000187:drug effects / Q000473:pathology; D019048:Prostatic Intraepithelial Neoplasia / Q000201:enzymology / Q000473:pathology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D016271:Proto-Oncogene Proteins c-myc; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases